| Abstract|| |
Post-transplant hypertension is a major risk factor for graft loss and patient survival; therefore, hypertension following renal transplantation must be treated strictly. There seems to be a strong association between hypertension, total body water (TBW) and dry weight. In this study, we report the relationship of body water and body composition with hypertension in post-renal transplant patients. Forty-five post-transplant patients were enrolled in the study. Blood pressure (BP) was labeled as controlled if BP was 120/80 mm Hg and not under good control if BP was above 120/80 mm Hg. Based on the number of antihypertensive medications a patient was taking, patients were divided into two groups: Group 1 patients on one antihypertensive drug and Group 2 patients on more than one antihypertensive drug. Nutritional status of the patients was assessed. Body composition (water compartments, body fat and lean mass) was assessed using bioelectrical impedance analysis (BIA). Patient data were compared with 30 healthy volunteers. In patients, systolic BP was associated with TBW (P = 0.016), extracellular water (ECW Lt; r = 0.99), ECW% (r = 0.78) and diastolic BP with TBW% (P = 0.003), dry weight (r = 0.76) ECW% (r = 0.95) and percent intracellular water (ICW%) (r = 0.79). Compared with controls, ECW and ECW% was higher in patients, and the ICW% was less in patients. There was significant difference in the actual weight of the patients and BIA-derived dry weight, although patients were clinically not edematous. The study showed a significant increase in diastolic BP with increase in dry weight. Significant difference in TBW was observed when the patients were grouped on the basis of the antihypertensive medication a patient was taking (one antihypertensive drug versus more than one antihypertensive drug). This study also showed an association between hypertension and overhydration. BIA may be a useful tool for the clinical assessment of overhydration in non-edematous patients.
|How to cite this article:|
Saxena A, Sharma R K. Hypertension in post-renal transplant patients: Pilot study. Saudi J Kidney Dis Transpl 2014;25:22-8
| Introduction|| |
Hypertension in kidney transplant recipients (80-90%), who still have their native kidneys present in situ particularly in those with chronic glomerulonephritis,  is a major "traditional" risk factor for atherosclerotic cardiovascular disease, which is the leading cause of premature death and a major factor in death-censored graft failure in transplant recipients. Blood pressure (BP) achieved after transplant is related inversely to post-operative glomerular filtration rate (GFR), with many patients experiencing a significant improvement in BP control with fewer medications within months of surgery. However, the benefits of improved GFR and fluid status may be affected by the immunosuppression regimen. , In transplant recipients, hypertension is usually defined as BP > 140/90 mm Hg or if a patient is on treatment with antihypertensive drugs.  ,  Most notable is the role of calcineurin inhibitors in promoting hypertension, cyclosporine more so than tacrolimus. Before the introduction of cyclosporine as a maintenance immunosuppression in 1983, post-transplant hypertension was seen in less than half of all patients. Since the introduction of calcineurin inhibitors, however, systemic hypertension is now found in 70-90% of recipients. ,,,,,,,, The National Kidney Foundation Task Force on cardiovascular disease recommends that the goal for therapy should probably be ≤135/85 mm Hg for renal patients without proteinuria and possibly ≤125/75 mm Hg for patients with proteinuria. , There are several causes of hypertension in transplant patients, such as pre-transplant factors [pre-existing hypertension and left ventricular hypertrophy (LVH), body mass index (BMI), primary kidney disease (native kidneys)], donor related (elderly and female donor, hypertensive donor, use of right-sided kidney), transplant related (prolonged ischemia time, delayed graft function), immunosuppressive therapy (calcineurin inhibitors, corticosteroids), renal transplant artery stenosis, renal outflow obstruction, renal transplant dysfunction (chronic allograft nephropathy and glomerulonephritis) and extracellular fluid volume expansion.  Severe renal artery stenosis may also lead to refractory salt and water retention and fluid overload with congestive heart failure and hypertension, mediated primarily due to extracellular fluid volume excess.  In normal subjects barring daily 5% fluctuation, total body water (TBW) is constantly maintained. TBW is largely altered in diseased patients, especially those with renal insufficiency. Bioelectrical impedance analysis (BIA) is emerging as a non-invasive, inexpensive bedside tool for estimating body composition and water compartments in health and in disease. With the advent of multifrequency analyzers, non-invasive analysis of body fluid compartments has now become possible. The ability to use this technique to accurately measure volume compartment size has many potential clinical applications.  This study was undertaken to investigate the potential relationship of body water with hypertension in stable post-renal transplant patients using wrist-to-ankle multifrequency BIA (WBIA).
| Subjects and Methods|| |
We conducted a cross-sectional study on post-transplant patients who had undergone renal transplant between the years 1997 and 2008 at SGPGIMS, Lucknow, and were on regular follow-up in the outpatient department. Forty-five adult patients (41 males; 4 females) were enrolled in the study. Enrollment was based on inclusion criteria, which included adult patients of both sexes with good urine output and nutritional status. All the patients were on a cyclosporin-corticosteroid-azatioprine (CCA) based combination immunosuppressive drug therapy. Patients were on antihypertensive medications (minimum one drug and maximum four drugs). BP was labeled as controlled if BP was ≤ 120/80 mm Hg and not under good control if BP was > 120/80 mm Hg. Based on the number of antihypertensive medications a patient was taking, patients were divided into two groups: Group 1 patients on one antihypertensive drug and Group 2 patients on more than one antihypertensive drug. Nutritional status of the patients was assessed using subjective global assessment (SGA) scores and malnutrition inflammation scores (MIS).  Urine output was in accordance with fluid intake (4.3 ± 2.2 L/day). Fluid intake was assessed by asking patients how many liters of fluid they ingested daily. Fluid adherence was determined if patients reported drinking the recommended three or more liters of fluid daily. Graft function was assessed using serum creatinine levels to estimate GFR using the Modification of Diet in Renal Diseases study equation, as recommended by the National Kidney Foundation's Kidney Disease Out-comes Quality Initiative clinical practice guide-lines. ,
None of the patients had malignancies. BIA measurements were performed using 915/916 Meltron BIOSCAN. Biochemical parameters for MIS included serum albumin and total iron binding capacity (TIBC). Patient data were compared with 30 healthy volunteers who had normal BP (<120/80 mm Hg). Anthropometric measurements included body weight, height, BMI and waist-hip-ratio. BIA-derived body composition parameters were phase angle, resting metabolic rate (RMR), TBW and percent (TBW%), extracellular water (ECW) and percent (ECW%), intracellular water (ICW) and percent (ICW%), ECW/ICW ratio, fat mass (FM) and percent (FM%), fat-free mass (FFM) and percent (FFM%), muscle mass, plasma fluid, interstitial fluid (Ints. fl) and dry weight (DW). Students' t test, Spearmans correlation and partial correlation were used for statistical analysis using SPSS version 10.0.
| Results|| |
Of the 45 patients, three patients were severely malnourished using SGA and MIS. The remaining patients had normal nutritional status. Waist-to-hip ratio was normal in both patients and controls. None of the patients were clinically edematous. Mean phase angle (measured with BIA) was 3.8 ± 1.6 in patients and 4.6 ±2.1 in controls. The difference was statistically significant.
Descriptive statistics of patients and controls is given in [Table 1]. Results show that there was a significant difference in the body composition parameters of controls and patients, except RMR, FFM and TBW [Table 2]. The difference in body composition was mainly attributed to the difference in the water compartments of patients and controls. In the patient group, systolic BP was associated with TBW (P = 0.016) and diastolic BP with TBW% (P = 0.003). Systolic BP had a significant positive correlation (partial correlation controlling for age and body weight) with ECW (Lt; r = 0.99) and ECW% (r = 0.78). Diastolic BP was positively correlated with dry weight (r = 0.76), ECW% (r = 0.95) and ICW% (r = 0.79).
|Table 2: Comparison of body composition parameters of patients and controls.|
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[Table 3] shows that based on BP (good control of BP versus BP not under good control), there was a significant difference in the FFM% (P = 0.033), FM (P = 0.047) and FM% (P = 0.031) in the two groups. Patients with uncontrolled BP had a higher FM and FM% and a low FFM%. When patient data was analyzed based on the number of antihypertensive medications a patient was taking (one antihypertensive drug versus more than one antihypertensive drug), a significant difference in the TBW was observed (X TBW 31.57 ± 4.0 Lt and 34.6 ± 4.1 Lt; P = 0.04) in the two groups. TBW was significantly less in patients who were on one antihypertensive medication.
|Table 3: Difference in fat and fat-free mass of patients based on blood pressure.|
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| Discussion|| |
Kidney function is central to secure the extra cellular milieu constancy required for adequate cell functioning. This balance is obtained by adjusting urinary excretion of water and electrolytes to match the net intake and endogenous production and the excretion of catabolic products such as urea, creatinine, uric acid, etc. ,,,,,,, Several studies with renal patients have investigated the relationship between hypertension and fluid overload. Fluid compartments have an important role in dynamics of hypertension. Hypertension in renal allograft recipients is a common problem arising from multiple factors. , For many years, it has been known that hypertension as a potent cardiovascular risk factor is associated with impaired patient and graft survival, although the nature of this relationship has not been clearly delineated.
Opelz et al , demonstrated a striking association between systolic and diastolic BP levels one year after a successful transplantation and kidney graft survival. In their follow-up study of >29,000 cadaveric renal transplant recipients, they found that increasing levels of systolic and diastolic BP post-transplant were associated with a graded increase of subsequent graft failure (P <0.0001). Chronic graft failure was also significantly associated with BP, even when patient death was censored (P <0.0001). Cox regression analysis established increased BP as an independent risk factor for graft failure. Whether substantial lowering of BP improves long-term transplant outcome remains unknown. However, a review of the data, focusing on those who were hypertensive (>150 mm Hg) at one year but were subsequently successfully treated to achieve a lower BP (<150 mm Hg after three years, showed that graft survival improved by ~15% during the following four years when compared with patients who remained hypertensive. 
In this study, 19 patients (42.7%) had good control of BP while 26 (57.3%) patients had poor control of BP. TBW and its distribution among compartments plays a critical role in predicting clinical outcome.  This study shows thatsystolic BP was associated with TBW (P = 0.016), ECW (Lt; r = 0.99), ECW% (r = 0.78) and diastolic BP with TBW% (P = 0.003), dry weight (r = 0.76) ECW% (r = 0.95) and ICW% (r = 0.79). Compared with controls, ECW and ECW% was higher in patients and ICW% was less in patients. Despite the fact that patients were clinically not edematous, there was a significant difference in the actual weight of the patients and BIA-derived dry weight of the patients. The BIA-derived dry weight was less than the actual weight, indicating that water compartments (fluid overload) may be expanded in post-transplant patients. There was no difference in the actual weight and the dry weight of the controls. This study shows a significant increase in diastolic BP with increase in dry weight. It may be advisable to restrict fluid intake (which was 4.3 ±2.2 L/day in this study) if the patient is on more than one antihypertensive medication. High FFM% indicates higher water content of the tissue. Also, in this study, patients had significantly higher FFM% compared with controls, indicating higher water content. A state of overhydration could confound body composition analysis if edema fluid is presumed to be tissue mass,  although edema was not clinically evident.
Our study supports the findings that ECW% is high in hypertensive patients.  In other words, volume overload is linked with hypertension. Patients who had well-controlled BP (< 120/80 mm Hg) with only one antihypertensive drug had less TBW compared with those who were on more than one antihypertensive medication.
Difference in the TBW observed between patients taking one antihypertensive medication versus more than one antihypertensive drug indicates that even post-transplant patients with stable graft function can have expanded water compartments, which may not be clinically obvious.
There was a significant difference in the FFM% (P = 0.033), FM (P = 0.047) and FM% (P = 0.031) of patients having good control of BP versus patients with BP not under good control. Patients with uncontrolled BP had higher FM and FM% and low FFM%. High FM and FM% and low FFMP in poorly controlled BP calls for reduction in dietary fat and salt intake. When patient data were analyzed based on the number of antihypertensive medications a patient was taking (one antihypertensive drug versus more than one antihypertensive drug), significant difference in the TBW was observed (X TBW 31.57 ± 4.0 Lt and 34.6 ± 4.1 Lt; P = 0.04) in the two groups. TBW was significantly less in patients who were on one antihypertensive medication.
BMI is related to both fat and muscle mass. High fat content is seen in individuals with high BMI. From a nutritional point of view, our patients had low (but normal) BMI, FM, FM% and muscle mass and high FFM% compared with controls. Low fat mass compared with controls could be the earliest nutritional change detectable in patients, which supports similar studies.  Patients with controlled BP were nutritionally better compared with those with uncontrolled BP as reflected from FFM%, FM and FM%.
Identification of modifiable factors causing hypertension and concurrent medical conditions, and measurement of GFR, cyclosporine/tacrolimus blood levels and magnitude of proteinuria are essential to tailor treatment for an individual patient. For pharmacological therapy, diuretics and calcium channel blockers are first-line agents in patients on cyclosporine shortly after transplant. Reduction of immunosuppression will improve hypertension in some patients, but entails a potential risk of rejection or graft loss. , The "protective" effects of ACE inhibitors have been attributed, among several other factors, to a reduction in intra-glomerular pressure. This may be of particular interest as it has been proposed that progressive graft failure resulting from chronic allograft dysfunction may be associated with glomerular hyperfiltration and hypertension due to an inadequate nephron mass. ,,,
Besides the BP-lowering effect of calcium channel antagonists (CCA), these drugs also efficiently counteract the intrarenal vasoconstriction associated with Cyclosporin-A (CiA) treatment (and possibly tacrolimus).  Their effect on renal hemodynamics may also reduce long-term CiA nephrotoxicity.  Clinical studies have suggested that use of CCAs in renal transplant patients receiving CiA may be associated with a reduction in both delayed graft function and acute rejection episodes, and possibly also a better long-term graft function. However, a meta-analysis of 21 studies published in 1994 concluded that results were conflicting. 
In summary, our study confirms the association between hypertension and overhydration as assessed by BIA. BIA may thus be a useful tool  that is inexpensive and simple to use for clinical assessment of fluid overload in non-edematous post-renal transplant patients and for dietary intervention such as fluid, salt and fat restriction. Loop diuretics are very useful when managing hypertensive patients with edema and/or hyperkalemia. Lifestyle modifications, such as weight loss, increasing regular exercise and sodium restriction, may be helpful, although such a recommendation is not supported by clinical trial evidence after transplant. Care should be tailored to the need of the individual and therapy should be goal oriented.
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Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 260014
[Table 1], [Table 2], [Table 3]